Fig. 9.

Block of inactivation-deficient hNa_v1.5-CW ramp Na⁺ currents by lacosamide. (A) Superimposed ramp Na⁺ currents of inactivation-deficient hNa_v1.5-CW Na⁺ channels were generated by a 1-second ramp stimulus from −140 to +50 mV in the absence (control) and presence of 300 µM lacosamide (dashed line). The inward Na⁺ currents appeared at the activation threshold near −75 mV and reversed to the outward direction at the reversal potential of approximately −10 mV. About 60% of currents were blocked at −30 and +50 mV, where the inward and outward Na⁺ currents reached the maximal values. (B) Superimposed ramp currents of BTX-modified hNa_v1.5 wild-type Na⁺ channels were elicited by the same pulse protocol as in A without (control) and with 300 µM lacosamide present (dashed line). One thousand repetitive pulses (+50 mV for 20 milliseconds at 2 Hz) were applied earlier to facilitate BTX binding with wild-type hNa_v1.5 Na⁺ channels. These BTX-modified ramp Na⁺ currents were completely resistant to 300 µM lacosamide. The inward BTX-modified ramp Na⁺ currents appeared around −120 mV because of the leftward shift of the activation threshold by BTX.